Encapsulation within a soft capsule of a solution or dispersion of a nutritional or pharmaceutical agent in a liquid carrier offers many advantages over other dosage forms such as compressed, coated or uncoated solid tablets or bulk liquid preparations. Encapsulation of a solution or dispersion permits accurate delivery of a unit dose, an advantage which becomes especially important when relatively small amounts of the active ingredient must be delivered, as in the case of certain hormones. Such uniformity is more difficult to achieve via a tableting process wherein solids must be uniformly mixed and compressed, or via incorporation of the total dose of active ingredient into a bulk liquid carrier which must be measured out prior to each oral administration.
Soft capsules, most commonly, soft gelatin capsules, provide a dosage form which is more readily accepted by patients, since the capsules are easy to swallow and need not be flavored in order to mask the unpleasant taste of the active agent. Soft capsules are also more easily transported by patients than bulk liquids, since only the required number of doses need be removed from the package.
Soft encapsulation of drugs further provides the potential to improve the bioavailability of pharmaceutical agents. Active ingredients are rapidly released in liquid form as soon as the gelatin shell ruptures. Complete disintegration of the capsule is not necessary for the active ingredients to become available for absorption, unlike the case of tableted compositions. Also, relatively insoluble active ingredients can be dispersed in a liquid carrier to provide faster absorption.
Traditionally, both soft and hard-shell capsules have been manufactured using mammalian gelatin as the material of choice for producing the capsule envelope. The rotary die process developed by Robert Scherer in 1933 for producing one piece soft capsules utilized the unique properties of gelatin to enable a continuous soft capsule manufacturing process. The inventive, gelatin-free composition disclosed in this patent application is especially useful in the rotary die method of soft capsule manufacture.
Conventional manufacturing of soft capsules using the rotary die process utilizes mammalian gelatin in a process essentially as follows. Dry gelatin granules are combined with water and suitable plasticizers and the combination is then heated under vacuum to form a molten gelatin mass. The gelatin mass is held in its molten state while being formed or cast as films or ribbons or casting wheels or drums. The films or ribbons are fed under a wedge and between rotary encapsulation dies. Within the encapsulation dies, capsules are simultaneously formed from the films or ribbons, filled, cut and sealed. The seals are formed via a combination of pressure and heat as the capsule is filled and cut. Rotary die manufacture of soft gelatin capsules is disclosed in detail in The Theory and Practice of Industrial Pharmacy (Lachman, Lieberman and Kanig, Editors), 3rd Edition, published by Lea & Febiger. A good description of gelatin encapsulation techniques can also be found in WO 98/42294 (PCT/GB98/00830).
Gelatin formulations used to produce films suitable for making capsules within the rotary die process typically contain between 25% to 45% by weight mammalian gelatin. Levels below 25% by weight tend to lead to poor sealing of the capsule. The physical properties of the gelatin film are critical to the economic production of soft capsules. For example, the film must be strong enough to survive manipulation in the encapsulation machine, provide good sealing properties at temperatures below the melting point of the film, evidence rapid dissolution in gastric juices, and have sufficient elasticity to allow for the formation of the capsule. The wholly non-animal composition of the present invention meets all of these requirements without the use of mammalian gelatin, and surprisingly evidences several improved properties.
The composition according to the present invention, like mammalian gelatin, has many properties that favor its use in soft capsule manufacture. One important property of the inventive compositions with respect to the rotary die process is the ability of the compositions to be cast to form films that are mechanically strong and exhibit elasticity sufficient to allow the film to stretch during filling. In other words, the inventive films have dimensional stability, elasticity and strength adequate for use in a continuous commercial process.
Another important and unique property of the inventive compositions is that the films forming the two halves of the capsule will fuse together during the filling and cutting process when subjected to sufficient pressure and elevated temperature. This fusing together relies on a particular property of the films that allows fusion under conditions of elevated temperature, supplied by the injection wedge, and pressure, supplied by the rotary cutting dies. The temperature at which fusion of two opposing films occurs should be below the melting point of the film, i.e., the fusion or sealing temperature is less than the melting point of the film composition. It has proven difficult to find this combination of properties in other polymer systems. Thus, most proposed substitutes for mammalian gelatin have failed due to a lack of one or more of these properties. This is the main reason why mammalian gelatin has been used almost exclusively as the shell forming material in soft capsule manufacture.
The property of fusion temperature being lower than melting temperature is crucial to the sealing of capsules using the continuous rotary die process. If the fusion and melting temperatures are about the same, the film will nearly completely melt as it passes through the wedge and the rotary die. At this temperature, the film loses its structure. As a result, capsules cannot be produced.
Disadvantages of mammalian gelatin includes the cost and continuity of supply. Gelatin has a variety of other drawbacks. For example, bovine sources are somewhat unattractive to individuals that prefer vegetarian food sources. Also, gelatin is prone to cross-linking, either caused by aging or due to reaction with compounds such as aldehydes. Cross-linking reduces the gelatin insoluble in gastric fluids, a generally undesirable quality for soft capsules. Thus, there is a need in the soft capsule industry for a replacement for the gelatin based compositions.
Other hydrocolloids form films but they lack the attributes of mammalian gelatin required to allow their use in the rotary die process. For example, a variety of modified food starches such as those available from Grain Processing Corporation as Pure-Cote®, are low viscosity starches that provide film-forming and adhesive properties. Such starches form clear, flexible films that are fast drying and flavor free. These materials are suitable as binders for seasonings on snacks and cereals and as smooth, glassy coating agents for confections and baked goods. However, these materials are unable to form hydrated films with the requisite strength and elasticity required for use in the rotary die process. Further, films made entirely from starch have insufficient elasticity and strength to be transferred from the casting drum to the rotary dies. Also, the films adhere too tightly to the casting drum, further diminishing transferability. Thus, compositions are needed that mimic the behavior and characteristics of mammalian gelatin while overcoming its shortcomings.